BEE 4530 - 2017 Student Papers

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    3D modeling of aflibercept transport in the vitreous humor
    Li, Kevin; Limjoco, Matthew; Zarate, Jason (2017-05-11)
    Aflibercept is an anti-vascular endothelial growth factor (anti-VEGF) drug used to treat several retinal diseases such as macular degeneration. It accomplishes this by binding and inhibiting VEGF, which is the growth factor that is responsible for abnormal blood vessel growth. Overexpression of VEGF can lead to interference with the macula, and subsequent vision loss. Aflibercept is prescribed to treat macular degeneration due to VEGF overexpression. It is administered via intravitreal injection. Analysis of the transport of aflibercept through the vitreous humor is critical to understanding whether or not patients are receiving appropriate amounts of drug at the macula boundary, where the abnormal growth of blood vessels is contributing to macular degeneration. This study will assess if the current market dose of aflibercept is successfully inhibiting VEGF for an appropriate time period. The scope of analysis involved construction of a three-dimensional geometry of the vitreous humor in COMSOL, an implementation of physical properties and parameters of the vitreous humor and aflibercept, an illustration of key results, a sensitivity analysis on certain parameters, and a validation of the COMSOL implementation. The analysis was conducted for a 3D diffusion problem, coupled with convection. Convection is due to pressure-driven flow, a result of the inherent pressure difference in the vitreous humor. Degradation or inactivation of aflibercept was also considered by modeling the second-order binding of aflibercept to VEGF. The distribution of aflibercept throughout the vitreous humor was successfully determined. Due to asymmetry in the injection site, or the placement of drug, it was found that the distribution of drug is asymmetric at early times, and becomes more uniform at later times. A similar result was found at the macula boundary, which is the target area of interest for this study. It was also shown that VEGF concentration is successfully inhibited upon the introduction of aflibercept. Based on the model, VEGF began to accumulate after initial suppression within 20 to 40 days of aflibercept injection. This coincides with the recommended interval between aflibercept injections, which is 28 days. Improvements in future model implementation could provide a result that more accurately represents the transport of aflibercept in the eye. These improvements include implementing an initial injection velocity when aflibercept is introduced, and the use of a more realistic geometry, such as an MRI scan, to build the geometry in the COMSOL model.
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    Saving the Sea Turtles: How Climate Change Affects Loggerhead Populations
    DeLorenzo, Lauren; Jackson, Samantha; Ring, Katherine; Sutton, Allison (2017-05-11)
    An ample amount of research has been conducted on how nest temperatures affect the sex of sea turtle hatchlings, but little has been done on how heat transfer contributes to the temperature. For the purpose of determining if heat transfer could be modeled, Loggerhead sea turtles (Caretta caretta) in Southern Florida were examined. Further analysis of nest temperature under conditions associated with climate change can predict potential effects in the future on Loggerhead and other sea turtle populations. This paper assumes that research and modeling of the heating process can lead to a better understanding of what contributes to nest temperature. The nest was approximated as one spherical homologous domain with weighted egg and air properties, located at 0.35 m below the surface of the sand. Conditions affecting temperature of the nest include solar radiation on the sand, convective heat transfer at the surface of the sand, and metabolic heat generation in the eggs. Hourly weather data from locations in Southern Florida was collected and used to simulate a varying boundary condition at the sand surface from air temperature, wind speed, and solar radiation. Metabolic heat generation from the eggs was based on data from another species of sea turtle. Two-dimensional axisymmetric heat conduction through the sand and nest was modeled using the commercial analysis software COMSOL Multiphysics. The model was validated by comparing the resulting Loggerhead nest temperature over time with experimental data from another location in Florida. Analysis of parameter sensitivity was conducted by varying the density, specific heat, and thermal conductivity of both the egg mass and sand. Changes in all of these parameters by 20% produced negligible effects on nest temperature. Varying the heat transfer coefficient to reflect the minimum and maximum air temperatures found in Southern Florida did not have a noticeable impact on nest temperature. Sensitivity of solar radiation was considered in applying shading conditions. The model was also used to predict potential effects from climate change by varying the top boundary condition. The model was used to observe how variation of environmental conditions, especially the projected increase of temperature due to climate change, affects the model and destabilizes the ratio between males and females. The results indicated that average nests laid in peak nesting seasons tend to produce a female-dominated clutch. A 1 to 4 °C increase in air temperature, as predicted by global warming trends, could give rise to potentially dangerous nest temperatures and exclusively female clutches. Shading has a drastic effect on nest temperature and can act to stabilize the sex ratio in global warming scenarios. In a broad sense, any species with temperature dependent sex determination can feel the effects of climate change, making this model especially important for coming years. This study aims to examine the causes of nest temperature variation, and explore viable solutions to potentially harmful effects from climate change. More research and global attention on the harmful consequences of climate change impacting species is critical.
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    Treating Osteoporosis: Localized Drug Delivery into Femur
    Anaya, Gustavo; Jackson, Jennifer; Roga, Zachary; Wu, Andy (2017-05-17)
    Bisphosphonates (BPs) are used to mitigate osteoporosis in patients who are at high risk for bone fractures. Common methods of administration of BPs rely on systemic delivery, which can lead to abdominal discomfort and unwanted concentrations of drug in other areas of the body. However, there is a limited understanding of the diffusion of BPs via localized delivery from scaffolds. This study investigates the diffusion of alendronate, a commonly used BP, from a scaffold into bone. A model for diffusion with fluid flow was constructed using the commercially available computational software COMSOL. The femur bone is approximated as a 3D cylinder of length 0.1 m with four layered subdomains: scaffold, periosteum, compact bone, and marrow. The layers are of radius 0.0002 meters, 0.00022 meters, 0.001 meters, and 0.0138 meters respectively. BPs have a diffusion constant of 115·10-12 square meters per second, 2.44·10-10 square meters per second, 2.44·10-10 square meters per second, and 1·10-12 square meters per second respectively in the four layers of the domain. The periosteum and compact bone have capillaries that run the length of the domain. These are modeled as randomly distributed identical cylinders running the length of the domain with a unidirectional fluid flow of 5·10-5 meters per second with a fluid density of 1060 kilograms per cubic meter. The initial conditions are concentration of 0 everywhere expect for the scaffold subdomain which has an initial concentration of 0.018 moles of alendronate per cubic meter of bone. These values can be found in Appendix A, Table 2. The results of this model show the concentration of bound alendronate in the bone reaches an effective concentration of 1·10-4 moles per cubic meter before 10 hours. We have also found the bound alendronate fraction has a low dependency on the initial scaffold concentration with the bound alendronate fraction at over 90% alendronate clearance time being over 0.8 for varying initial concentrations. Sensitivity analysis revealed that bound alendronate concentration is not dependent on the diffusivities of compact bone or marrow, or on blood velocity, but is highly dependent on initial scaffold concentration and the binding rate constant of alendronate to bone. This model provides a comprehensive understanding of how BPs move through the bone and the time it takes for BP concentration to reach certain levels in the bone. This in turn allows for more accurate dosage times and amounts in order to provide the most efficient bone loss prevention.
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    What Happens When You Swallow a Hydrogel Pill?
    Carroll, Katherine; Connolly, Rachel; Hearn, Kaitlin; Yasin, Imran (2017-05-16)
    The scientific world has limited knowledge on tablet properties, so scientists want a reliable method to investigate these properties and their effects on the drug release profile. We developed a model that is based on experimental data and used for various matrix combinations. In COMSOL, we modeled how the three phases of a hydrogel – swelling, eroding and diffusing – facilitated the overall delivery of a given drug. We used the principles of mass transport and solid mechanics, respectively, to model the delivery of the drug in the body as well as the erosion and swelling of the hydrogel. In COMSOL, a university licensed software program, we modeled a semi-overall shaped hydrogel through a 2D axisymmetric model. We initially modeled the geometry at its initial, non-deformed shape with the mass fractions of the water, drug, and polymer are at their initial values. The geometry deformed with time as swelling and erosion affect the polymer matrix. Using this geometry, we modeled and analyzed percent drug release, the mass of water inside the matrix, and mass of drug and polymer release over time. We then used past research data to evaluate and to understand texture analysis and to model phenomena of multiple diffusing species from a matrix. To validate our model, we compared our modeling outcomes with experimental results to understand how successfully our model depicts the experimental data. Finally, we conducted a sensitivity analysis to determine how various parameters independently affected our results. Based on our design objectives, our model aligned with our initial goals. We successfully modeled the swelling and erosion of a hydrogel matrix over time. We also effectively modeled the release of the drug from the polymer-drug matrix. We combined these two processes in COMSOL. With the results, we were able to post-process our solution by refining our mesh and conducting a sensitivity analysis. The results of our study are limited to a set of assumptions made about the geometry. These assumptions include the use of a 2D model for a 3D delivery process and negligible velocity in the environment. Therefore, while the model provides a realistic analysis of hydrogel drug delivery, some environmental factors may influence the overall outcome for each user. Using mass transport and solid mechanics to model the three phases of the hydrogel, we were able to create a realistic model of this drug delivery process. Our model allows scientists and engineers investigate various matrix properties and their effects on the tablet's drug release profile. Without invasive procedures, they can use our model to design the optimal tablet for their specific pharmaceutical need. Therefore, our model is a necessary tool for the scientific world to develop cost and time efficient hydrogel drug-matrices.
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    Density Driven Spread of Anesthesia in Cerebrospinal Fluid
    Bollapragada, Rajesh; Chen, Victor; Khan, Priyanka; Pierides, Michael (2017-05-17)
    Intrathecal administration of anesthesia is performed for purposes of sensory and motor nerve blockage during surgeries to the abdomen and lower extremities. The spread of anesthesia is primarily based on the injection velocity, concentration, and density of the drug and determines which spinal nerves are blocked and the duration for which the block is maintained. As abdominal surgeries differ in the nerves that require blockage and the duration the block is required, the properties of the anesthesia, such as density, concentration, and injection velocity must be made unique for a given surgery to produce the optimal blockage for that procedure. Anesthesiologists refer to the density ratio of the anesthesia to the cerebrospinal fluid as the baricity. Hyperbaric anesthesia, which is more dense than cerebrospinal fluid, tends to diffuse downward in the direction of gravity. Hypobaric anesthesia, which is less dense than cerebrospinal fluid, tends to diffuse upward, against gravity. The baricity of anesthesia can be increased by the addition of dextrose and decreased by the addition of distilled water. While the baricity of the anesthesia affects its spread and the nerves that are blocked, the concentration of the drug affects the duration of blockage. In many cases, the degradation rate of intrathecal anesthesia is proportional to the concentration of the drug in the spinal canal and a higher concentration of the drug would increase the duration of blockage. However, the spread and dosage of anesthesia must be carefully monitored throughout the procedure as slight fluctuations in these parameters can put the patient at risk of cardiac complications such as hypotension, bradycardia, and potentially death. The density-driven spread and duration of blockage by the anesthesia bupivacaine were modelled with respect to its baricity, concentration, and injection pressure. The results demonstrated that hyperbaric anesthesia tended to diffuse in the direction of gravity while hypobaric anesthesia tended to diffuse against gravity. An objective function was also created that measured the harm the anesthesia did to the patient. The safe range of anesthesia concentrations was found to be 2.5 to 7.5 mg/mL. The optimum injection pressure was found to be 915,279 Pa, which is comparable to the pressure of injection. However, while baricity had a great effect on the spread of the drug, it appeared to have no noticeable effect on the block provided by anesthesia.
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    Betamethasone Phosphate Drug Delivery by Biodegradable Ocular Implant
    Chari, Tara; Li, Catherine; Varghese, Rebecca; Yang, Qiuwei (2017-05-17)
    Biodegradable implants have been steadily gaining popularity, offering safer, more efficient alternatives to common therapeutics. Currently, most ocular implants that are used for sustainable drug delivery are non-biodegradable. In addition to the eye being a sensitive area, the likelihood of complications increases when multiple surgeries are performed to remove the implant as well as insert it. Biodegradability of the implant can eliminate these removal complications. Using COMSOL® Multiphysics, we modeled the delivery of betamethasone phosphate (BP) from a biodegradable implant that is placed in the scleral layer of a human eye. As a glucocorticoid, BP is used to reduce inflammation in the tissue layers surrounding the sclera. We used a 2D axisymmetric geometry to represent the eye with the implant and focused on the delivery of BP to the retina. The implant’s bulk erosion and mass transfer dynamics resulted in an initial spike of BP release followed by a slow, gradual depletion of the remaining drug. The initial size and location of the implant in our model were taken from those of similar implants tested in rabbit eyes. Upon finding that BP concentration exceeded the desired range in the retina, we optimized the location and size of our implant for drug delivery in the human eye. After optimization, an effective concentration in the retina was maintained for 34 days. The model was validated with experimental data for BP release from implants in the rabbit eye, which is an accurate model for drug pharmacokinetics in the human eye. Our results suggest that this biodegradable ocular implant is a viable option for drug delivery in the human eye.
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    Focused Ultrasound Induced Heating for Drug Delivery in Cancer Therapies
    Datta, Amita; Dreiman, Gabe; Livermore, Grace; Wang, Alice (2017-05-18)
    Many treatment options are available in eliminating tumors including surgery, radiation, and chemotherapy. These treatments, however, have heavy financial constraints and/or significant systemic side effects. Focused ultrasound (FUS) is a new method that has been implemented for targeted cancer treatments. Chemotherapeutic drugs are stored in temperature sensitive liposomes and injected near the target tumor area. FUS is used to heat the target tissue to a temperature range that causes the liposomes to burst and release their drugs. This methodology allows targeted drug delivery to the tumor region while sparing the surrounding tissue, preventing the systemic side effects of traditional chemotherapy. We used COMSOL to optimize the duty cycle and pulse repetition frequency (PRF) of FUS to maximize induced heating in a tissue analog, a bovine serum albumin phantom, from 21°C to a specified temperature range, 23-28°C, while minimizing heating to the surrounding tissues. We used a homologous tissue-mimicking phantom to have uniformity in parameters and to compare our results with the experimental results from literature [1]. In tissue, body temperature is 37°C and the liposomes are engineered to break at temperatures between 39°C and 44°C [1]. Therefore, we used a different initial temperature for the phantom but the same change in temperature. In the model, as the pressure waves from the ultrasound transducer pass into the phantom, some energy is lost. This attenuation of acoustic energy was assumed to be equal to the heat energy gained by the phantom and thus was used as a heat source term. We were able to determine the optimal duty cycle and PRF of the FUS to reach a high enough temperature that would release chemotherapeutic agents from the liposomes into only the target region of the phantom.
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    Laser Ablation for Cardiac Tissue Oxygenation
    Dokko, Jacqueline; Eun, Chae Young; Kiembock, Conor; Wang, Qikun (2017-05-18)
    The leading cause of myocardial infarctions, commonly known as heart attacks, is the reduced blood flow to the heart muscle due to plaque buildup in the coronary artery. Transmyocardial laser revascularization (TMLR) is one of the more recently used procedures to treat blocked arteries when traditional treatments such as vascular stents and bypass grafting surgery are not suited for the patient. TMLR involves a CO2 laser heating process to ablate heart tissue and create channels through the entire myocardium wall. The new channels throughout the heart then facilitate transport of oxygenated blood from the ventricle to the oxygen-deprived heart tissue shortly after the procedure. After a long time, the heart can revascularize the affected area, healing the channels while simultaneously creating new blood vessels through a process called angiogenesis. Eventually the new blood vessels replenish oxygen in the heart tissue. Our project goal was to model the tissue ablation and oxygenation process of TMLR and optimize the channel-making procedure. Our quantities of interest were healthy tissue damage and short-term oxygen transfer, which we wanted to minimize and maximize respectively. We used COMSOLr to model the laser heating via the heat transfer module and simplified the procedure domain to a two-dimensional, axisymmetric geometry. Our model simulates the channel formation process through the use of the "Deformed Geometry" feature in COMSOL. Next, we analyzed the oxygen transfer process from the inflowing blood to the surrounding tissue on another two-dimensional, axisymmetric model with a mass transfer equation. Additionally, we coupled fluid flow equations to the mass transfer governing equation to observe the effects of blood flow on the oxygen transfer to the tissue. In optimizing this procedure, we looked at various combinations of laser power and spot size radii, the two factors that can be varied to deliver different laser heat fluxes to the tissue. Using the two simulation models, we concluded that the optimal laser power is in the range of 538 W to 600 W and optimal spot size radius is 0.55 mm. These laser configurations take into account the negative effects of overheating and the positive effects of oxygen transfer. The results of this report are significant for the patients who suffer from heart attacks and for the surgeons who are in search of better solutions. The laser heating procedure discussed in this report can serve as an alternative treatment for patients who have already received traditional methods of treating blocked arteries but did not experience significant changes in their symptoms. From the results of our models, we provide promising evidence that revascularization through TMLR successfully oxygenates the myocardial tissue in the short term.
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    Optimizing Shear for Neural Stem Cell Differentiation
    Steinhagen, Dustin; Ravelo, Gabrielle; He, Sophia (2017-05-19)
    Neural stem cells (NSC) have great potential for use in treatments for neurological disease by replacing damaged brain tissue via transplantation therapies. Growing NSC can be challenging, since the environment that the multipotent stem cells are grown in needs to be tightly controlled to ensure they differentiate into the desired stem cell line. Different methods have been considered to ensure the differentiation of these multipotent mesenchymal stem cells (MSC) into NSC, and finding the best design of bioreactor for growing any given stem cell line is an ongoing topic of inquiry in biomedical research. The purpose of our project was to model a scalable suspension bioreactor in COMSOL Multiphysics that can be used to obtain a high enough yield of NSC for therapeutic applications. This was accomplished by providing the right shear environment for the NSC to differentiate in. We modeled fluid flow through the bioreactor using the Navier-Stokes equation, with Darcy flow through the filter near the middle of the bioreactor. We then adjusted the inlet volumetric flow rate to ensure that NSC are subjected to optimum shear rates during their residence time in the bioreactor. We performed a sensitivity analysis on our bioreactor and found that the shear distribution of the bioreactor is most sensitive to the density of the medium used to grow the cells. In this report, we start by exploring some of the most current challenges faced when using different types of bioreactors to grow NSC, as well as some research that inspires our bioreactor design to be better than current options. A layout of our perfusion bioreactor is then detailed by a schematic, governing equation and boundary conditions before being modeled in COMSOL. Shear profiles are shown and discussed in the results section. Fluid control has major implications for the internal environment of the bioreactor. We have shown that these aspects can be optimized to create a more suitable suspension environment for NSC incubation.